Open AccessJournal Article
Somatic Mutations in the Kinase Domain of the Met/Hepatocyte Growth Factor Receptor Gene in Childhood Hepatocellular Carcinomas
Won Sang Park,Seung Myung Dong,Su Young Kim,Eun Young Na,Min Sun Shin,Jae Ho Pi,Bum Jun Kim,Jeong Hoon Bae,Young Ki Hong,Kyo Sun Lee,Sug Hyung Lee,Nam Jin Yoo,Ja June Jang,Svetlana Pack,Zhengping Zhuang,Laura S. Schmidt,Berton Zbar,Jung Young Lee +17 more
TLDR
The results indicate that mutations of the tyrosine kinase domain of the MET gene may be involved in the acceleration of the carcinogenesis in childhood HCC.Abstract:
The MET protooncogene encodes a transmembrane tyrosine kinase identified as the receptor of a polypeptide known as hepatocyte growth factor/scatter factor. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the tyrosine kinase domain of the MET gene (exon 15-19) in 75 primary liver cancers. Three missense mutations were detected exclusively in 10 childhood hepatocellular carcinomas (HCCs), while no mutations were detected in 16 adult HCCs, 21 cholangiocarcinomas, or 28 hepatoblastomas. The extremely short incubation period from hepatitis B virus infection to the genesis of childhood HCC as compared with the adult HCC suggests that there may be an additional mechanism that accelerates the carcinogenesis of childhood HCC. Our results indicate that mutations of the tyrosine kinase domain of the MET gene may be involved in the acceleration of the carcinogenesis in childhood HCC.read more
Citations
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Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995.
Journal ArticleDOI
Molecular pathogenesis of human hepatocellular carcinoma
TL;DR: The malignant hepatocyte phenotype may be produced by the disruption of a number of genes that function in different regulatory pathways, producing several molecular variants of hepatocellular carcinoma.
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Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.
Selma Pennacchietti,Paolo Michieli,Maria Galluzzo,Massimiliano Mazzone,Silvia Giordano,Paolo M. Comoglio +5 more
TL;DR: It is shown that hypoxia promotes tumor invasion by sensitizing cells to HGF stimulation, providing a molecular basis to explain Met overexpression in cancer.
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Cabozantinib (XL184), a Novel MET and VEGFR2 Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth
F. Michael Yakes,Jason Chen,Jenny Tan,Kyoko Yamaguchi,Yongchang Shi,Peiwen Yu,Fawn Qian,Felix Chu,Frauke Bentzien,Belinda Cancilla,Jessica Orf,Andrew You,A. Douglas Laird,Stefan Engst,Lillian Lee,Justin Lesch,Yu-Chien Chou,Alison Joly +17 more
TL;DR: Treatment with cabozantinib is suggested to be a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.
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Drug development of MET inhibitors : targeting oncogene addiction and expedience
TL;DR: Recent progress in the development of molecules that inhibit MET function are discussed and their application in a subset of human tumours that are potentially responsive to MET-targeted therapies is considered.
References
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Journal ArticleDOI
Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification.
Steven K. Hanks,Tony Hunter +1 more
TL;DR: The eukaryotic protein kinases make up a large superfamily of homologous proteins, and a classification scheme can be founded on a kinase domain phylogeny, which reveals families of enzymes that have related substrate specificities and modes of regulation.
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Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
Laura S. Schmidt,Fuh Mei Duh,F. Chen,Takeshi Kishida,Gladys Glenn,Peter L. Choyke,Stephen W. Scherer,Zhengping Zhuang,Irina A. Lubensky,Michael Dean,Rando Allikmets,Abirami Chidambaram,Ulf S.R. Bergerheim,J. T. Feltis,C. Casadevall,A. Zamarron,M. Bernues,Stéphane Richard,C. J. M. Lips,McClellan M. Walther,Lap-Chee Tsui,Laura Geil,Mary Lou Orcutt,Thomas Stackhouse,J. Lipan,L. Slife,Hiltrud Brauch,Jochen Decker,G. Niehans,M. D. Hughson,Holger Moch,Stefan Storkel,Michael I. Lerman,W.M. Linehan,B. Zbar +34 more
TL;DR: The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.
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Molecular cloning of a new transforming gene from a chemically transformed human cell line
Colin Cooper,Morag Park,Donald G. Blair,Michael A. Tainsky,Kay Huebner,Carlo M. Croce,George F. Vande Woude +6 more
TL;DR: Molecular cloning of the transforming gene from a chemically transformed human osteosarcoma-derived cell line enables the gene to be mapped to chromosome 7 (7p11.4–7qter) and by direct hybridization to be shown to be unrelated to known oncogenes.
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Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors
TL;DR: It is concluded that the MET protooncogene is a cell-surface receptor for an as-yet-unknown ligand that is most homologous with the human insulin receptor and v-abl.
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Activating mutations for the Met tyrosine kinase receptor in human cancer
Michael Jeffers,Laura S. Schmidt,Noboru Nakaigawa,Craig P. Webb,Gregor Weirich,Takeshi Kishida,Berton Zbar,George F. Vande Woude +7 more
TL;DR: The results demonstrate that the Met mutants originally identified in human papillary renal carcinoma are oncogenic and thus are likely to play a determinant role in this disease, and raise the possibility that activating Met mutations also may contribute to other human malignancies.
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Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas
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